A normal artery typically is lined on its inner-side by a single layer of endothelial cells, the intima. The intima overlays the media, which contains only a single cell type, the vascular smooth muscle cell. The outer-most layer of the artery is the adventitia.
Neovascularization, or angiogenesis, is the growth and development of new arteries. It is critical to the normal development of the vascular system, including injury-repair. There are, however, conditions characterized by abnormal neovascularization, including diabetic retinopathy, neovascular glaucoma, rheumatiod arthritis, psoriasis and certain cancers. For example, diabetic retinopathy is a leading cause of blindness. There are two types of diabetic retinopathy, simple and proliferative. Proliferative retinopathy is characterized by neovascularization and scarring. About one-half of those patients with proliferative retinopathy progress to blindness within about five years.
Another example of abnormal neovascularization is that associated with solid tumors. It is now established that unrestricted growth of tumors is dependant upon angiogenesis, and that induction of angiogenesis by liberation of angiogenic factors can be an important step in carcinogenesis. For example, basic fibroblast growth factor (bFGF) is liberated by several cancer cells and plays a crucial role in cancer angiogenesis. The demonstration that certain animal tumors regress when angiogenesis is inhibited has provided the most compelling evidence for the role of angiogenesis in tumor growth.
It would be desirable to identify antiangiogenesis agents useful in treating the foregoing diseases.
Imidazoles are synthetic antifungal agents that are used both topically and systemically. Indications for their use include ringworm, tinea versicolor and mucocutaneous candidiasis. These compounds are believed to act by inhibiting ergosterol synthesis in the fungal cell wall, and when given topically, may cause direct damage to the cytoplasmic membrane.
The fungi comprise five widely differing classes of primitive flora, and the variation in cell physiology and biochemistry are extreme. As a result, most antifungal agents have a very narrow spectrum of antifungal activity.
Various imidazoles have been suggested as treatments for prostate cancer. The only one known to the applicants to have been tested is ketoconazole. Ketoconazole is an antifungal agent that, in high doses, inhibits testicular and adrenal synthesis of steroid hormones, including testosterone. The ability of ketoconazole to block steroid synthesis has prompted its use in the treatment of advanced prostate carcinoma because prostate cancer cells are highly dependent on testosterone. The major sites of action appear to be in the inhibition of 17-20 desmolase, partial blockade of 17-hydroxylase and marked inhibition of 21- and/or 11-hydroxylase, all major enzymes of the androgenic hormone synthetic pathways.
In the recent past, newer methods of androgen ablation for the treatment of metastatic prostate carcinoma have been developed as alternatives to the standard forms of therapy: oral estrogens and surgical castration. Luteinizing hormone-release hormone (LHRH) analogs, potent inhibitors of testosterone production, have recently emerged as major players in the long term treatment of advanced prostate cancer. In contrasts, ketoconazole has been found to be excellent for short-term usage prior to bilateral orchiectomy and when prompt therapeutic response is needed but orchiectomy cannot be performed. In high doses, ketoconazole causes castrate levels of testosterone within 24 to 48 hours; therefore, it is extremely useful in the initial medical treatment of patients with metastatic prostate cancer who need a prompt therapeutic response. Thus, ketaconazole has been used as a hormonal adjuvant for prostate cancer treatment; it reduces plasma testosterone to castration levels. Ketoconazole, as will be described below, is not useful for inhibiting endothelial and vascular smooth muscle cell proliferation associated with neovascularization.